The goal of this proposal for a Mentored Clinical Scientist Career Development Award is for the candidate to achieve expertise in immunology and study design so that she may become an independent investigator in Human Immunodeficiency-1 (HIV) translational research. The candidate's expertise in clinical Infectious Diseases and ongoing immunology basic science training makes her highly qualified for the Career Development Award. Dr. Nina Bhardwaj, the candidate's mentor for this application, is expert in dendritic cell biology and has authored more than 130 peer-reviewed publications and has mentored more than 35 trainees, including 4 recipients of the K award. Since being recruited to the Bhardwaj laboratory during her fellowship in Infectious Diseases, the candidate has already made important contributions to the field of HIV immunology. The candidate's career plan focuses on enhancing skills in immunology, virology, and experimental design to become an independent researcher. The candidate's proposed research project centers on the idea that HIV dysregulates plasmacytoid dendritic cells (pDC) to activate deficient adaptive immune responses while stimulating persistent interferon-alpha (IFNa) production, thought to contribute to pathogenic inflammation and chronic immune activation, the driver of AIDS. pDCs are antigen presenting cells that are specialized to produce IFNa and to activate adaptive immune responses. Although IFNa inhibits HIV replication in vitro, the production of IFNa by HIV-activated pDCs in vivo likely contributes more to HIV pathogenesis than to protection. The candidate has shown that pDCs isolated from acutely HIV-infected subjects produce markedly elevated IFNa upon stimulation with HIV, as compared to pDCs from healthy subjects, contributing to the "cytokine storm" of acute HIV. Moreover, the candidate has shown that HIV activates abnormally persistent IFNa production by pDCs. She has shown that endocytosed HIV virions are retained in pDC cellular compartments that activate IFNa signaling pathways instead of trafficking to pDC cellular compartments that activate pathways necessary for maturation, antigen-presentation, and negative feedback of IFNa signaling pathways. In this application the candidate proposes to 1) study whether pDCs from chronically HIV-infected subjects produce elevated IFN in response to HIV stimulation, whether the degree of excess IFN correlates with immune activation, and whether pDCs from HIV- infected subjects may be modulated to inhibit persistent IFN responses and to improve adaptive immune responses, and 2) discover why HIV is retained in early endosomes to stimulate persistent IFN production and to determine how this trafficking pattern may be manipulated to inhibit persistent IFN and to enhance antigen-presentation PUBLIC HEALTH RELEVANCE (provided by applicant): The vulnerable populations most affected by HIV infection would be better served by a preventive or therapeutic vaccine than by expensive and life-long antiretroviral medications. Improved understanding of how HIV interacts with the immune system is necessary to develop an effective HIV vaccine. We propose to define mechanisms by which HIV dysregulates the innate immune system, which will guide new strategies to maximize adaptive immune responses and limit immune activation.